GENETIC VARIABILITY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ANALGESICS (LAYERED MEDICINE)

Pain therapy, the most widely spread disorder, tends more as other diseases, to administration of drug molecules targeted to the affected tissue at the right dose, or to the patient or patient groups (personalized medicine). A decisive determinant of this strategy is the genetic one, which is to some extent the basis of the variability of pharmacokinetic and pharmacodynamic response to analgesics in the patient population. The differences in action and response to analgesics are due in these cases to hyperfunctional or nonfunctional uni-nucleotide gene polymorphisms encoding enzyme-modified transport proteins or receptors involved in the biotransformation and dynamics of analgesics. Genomic testing increases therapeutic efficacy and avoids adverse effects especially in patients with long-term therapies.   &nbsp

GENETIC VARIABILITY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ANALGESICS (LAYERED MEDICINE)

Pain therapy, the most widely spread disorder, tends more as other diseases, to administration of drug molecules targeted to the affected tissue at the right dose, or to the patient or patient groups (personalized medicine). A decisive determinant of this strategy is the genetic one, which is to some extent the basis of the variability of pharmacokinetic and pharmacodynamic response to analgesics in the patient population. The differences in action and response to analgesics are due in these cases to hyperfunctional or nonfunctional uni-nucleotide gene polymorphisms encoding enzyme-modified transport proteins or receptors involved in the biotransformation and dynamics of analgesics. Genomic testing increases therapeutic efficacy and avoids adverse effects especially in patients with long-term therapies.   &nbsp

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer’s disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer’s disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics

Exploring the Therapeutic Potential of Cannabinoid Receptor Antagonists in Inflammation, Diabetes Mellitus, and Obesity

Recently, research has greatly expanded the knowledge of the endocannabinoid system (ECS) and its involvement in several therapeutic applications. Cannabinoid receptors (CBRs) are present in nearly every mammalian tissue, performing a vital role in different physiological processes (neuronal development, immune modulation, energy homeostasis). The ECS has an essential role in metabolic control and lipid signaling, making it a potential target for managing conditions such as obesity and diabetes. Its malfunction is closely linked to these pathological conditions. Additionally, the immunomodulatory function of the ECS presents a promising avenue for developing new treatments for various types of acute and chronic inflammatory conditions. Preclinical investigations using peripherally restricted CBR antagonists that do not cross the BBB have shown promise for the treatment of obesity and metabolic diseases, highlighting the importance of continuing efforts to discover novel molecules with superior safety profiles. The purpose of this review is to examine the roles of CB1R and CB2Rs, as well as their antagonists, in relation to the above-mentioned disorders

Demonstrating the antinociceptive action of renin-angiotensin system modulators in mice

Research done in the present study belongs to a wider area of experimental determinations on nociception models, when using laboratory animals. Their aim is to determine the ED50 value (Efficient dose 50) in conditions of inflammatory (chemical stimulus) and non-inflammatory (thermic stimulus) antinociception of some renin-angiotensin system modulators: captopril, ramipril, candesartan. The experimental determinations were realized accordingly to bioethical regulations concerning laboratory animals. The study has used Swiss mice, weighing between 20-30g, being held in constant temperature (21°C ± 2°C) and a dark / light cycle of 12 hours (7.00 AM / 7.00 PM). The researched substances are administered as CMC-Na 0.1% suspensions in geometrical progression doses. The following nociception models have been used: abdominal constrictive response test, hot plate test, formalin test. The abdominal constrictive response test has been evaluated as quantal, the hot plate test and the formalin test have been interpreted as gradual. The regression line, the correlation coefficient and the interval of trust for each substance and studied model have been analyzed. The obtained ED50 values are compared to each other to evaluate the potency of the substances for each nociception model. The obtained data is used for realizing fixed-ratio antinociceptive combinations

Acute Toxicity and Pharmacokinetic Profile of an EU-GMP-Certified Cannabis sativa L. in Rodents

The conundrum of Cannabis sativa’s applications for therapeutical purposes is set apart by the hundreds of known and commercially available strains, the social, cultural and historical context, and the legalization of its use for medical purposes in various jurisdictions around the globe. In an era where targeted therapies are continuously being developed and have become the norm, it is imperative to conduct standardized, controlled studies on strains currently cultivated under Good Manufacturing Practices (GMP) certification, a standard that guarantees the quality requirements for modern medical and therapeutic use. Thus, the aim of our study is to evaluate the acute toxicity of a 15.6% THC: <1% CBD, EU-GMP certified, Cannabis sativa L. in rodents, following the OECD acute oral toxicity guidelines, and to provide an overview of its pharmacokinetic profile. Groups of healthy female Sprague-Dawley rats were treated orally with a stepwise incremental dose, each step using three animals. The absence or presence of plant-induced mortality in rats dosed at one step determined the next step. For the EU GMP-certified Cannabis sativa L. investigated, we determined an oral LD50 value of over 5000 mg/kg in rats and a human equivalent oral dose of ≈806.45 mg/kg. Additionally, no significant clinical signs of toxicity or gross pathological findings were observed. According to our data, the toxicology, safety and pharmacokinetic profile of the tested EU-GMP-certified Cannabis sativa L. support further investigations through efficacy and chronic toxicity studies in preparation for potential future clinical applications and especially for the treatment of chronic pain

Different modulatory effects of ammonium ions on angiotensin vascular actions in isolated rat aortic and renal arteries

In the present study, we were interested in the vascular effects of angiotensin II on perfused rings of the rat thoracic aorta and renal artery. Our results demonstrated different modulator alterations of these preparations induced by ammonium ions. Unlike the aortic rings, which exhibited only a reduction of angiotensin-induced contractility by NH4Cl, the renal artery preparations showed both activation of vasoconstriction and inhibition of vasorelaxation in the ring precontracted with phenylephrine or noradrenalin. These results are interpreted as a modulation by the ammonium ions of vascular reactions induced by the stimulation of the vasoconstrictor AT1 receptor on the one side and AT2 vasodilator receptors on the other. The potentiation of renal vasoconstriction accompanied by the reduction of angiotensin vasodilation by NH4Cl suggests the possibility of involvement from the blood flow and renal vascular tonus disturbances induced by ammonium ions during hyperammonemia of various causes

Validity and reliability of the Romanian version of the Hill-Bone compliance to high blood pressure therapy scale

Romania is considered a country with high cardiovascular risk, arterial hypertension and its complications accounting for about 60% of total deaths. The management of high blood pressure often involves a combination of both therapeutic regimens as well as lifestyle changes, to which patients have to be adherent. In order to assess patients adherence to professionals’ recommendations, validated tools are needed. The aim of our study was to translate, culturally adapt and validate the Hill-Bone Compliance to High Blood Pressure Therapy Scale into Romanian. The study included 215 participants from Iasi, North-Eastern Romania. The internal consistency of the instrument was measured with Cronbach’s alpha coefficient, while the construct validity was determined using exploratory factor analysis and principal component extraction with promax rotation. Sampling adequacy and appropriateness of data for factor analysis was measured using Kaiser-Meyer-Olkin (KMO) statistics and Bartlett’s test of sphericity. Our statistical analysis revealed a Cronbach’s alpha coefficient of 0.733 (73.3%) and a Kaiser-Meyer-Olkin (KMO) Measure of Sampling Adequacy of 0.697. The chi square test demonstrated that the overall perfect adherence was not significantly associated with the number of medications taken per day variable (p = 0.721). The Romanian version of the Hill-Bone Compliance to High Blood Pressure Therapy Scale demonstrated suitability for its use in evaluating adherence in the intended population

PAIN ANIMAL MODELS IN ALZHEIMER`S DISEASE

Animal models offer valuable tools for evaluating new therapeutic strategies for treatment of human diseases, as well for studying the pathological mechanisms involved in the disease processes. However, they reproduce, in general, just certain aspects of human diseases. In this way, there are numerous aspects of nociception studies, describing these tests as a simple matter of first accounting for the nature of the stimulus (electrical, thermal, mechanical, or chemical) and then describing the behavioural parameters that are measured, but assessments vary with the scale used, while also the scales can be very subjective. Thus, animals will withdraw an injured body part from a stimulus, where different levels of stimulation affect the latency or force of withdrawal. This withdrawal response is considered a measure of pain, which correlates highly with more integrative nocifensive behaviours (e.g. some behavioural signs are usually associated with pain), such as licking of the injured body part and guarding behaviour. Moreover, the vocalizations are important indicators of pain in several species. In this way, animals in pain may lick, bite, scratch, shake, or rub the site of injury, as described in reference works such as the Guidelines for the Care and use of Mammals in Neuroscience and Behavioural Research. In addition, it is important to mention that pain studies are affected by a wide range of modulatory factors, including sex, genotype and social communication, all of which must be taken into account when using an animal model